Effect of Intraoperative Blood Transfusion on Patient Outcome in Hepatic Transplantation FREE

IMPROVEMENTS IN patient selection, surgical techniques, postoperative management, and immunosuppression for orthotopic liver transplantation (OLT) have led to patient survival approaching 80% at 1 year.¹ While attempts have been made to identify factors affecting patient and graft survival, no set of uniform predictive variables has been described.^2- 5 The effect of intraoperative blood loss and transfusions on survival after liver transplantation has been assessed by several different centers, with most data showing a correlation between blood use and postoperative morbidity and mortality rates.^2- 3,6- 8 During a 3-year period, a substantial proportion of our adult patients underwent OLT without intraoperative transfusion of red blood cells (RBCs). These patients were compared with recipients who received at least 1 U of RBCs intraoperatively to determine the effect of not giving patients RBC transfusions on patient and graft survival rates after OLT.

Between January 1, 1992, and December 31, 1994, a total of 334 OLTs were performed at California Pacific Medical Center, San Francisco. Pediatric recipients (82 transplants) and retransplantations (27 transplants) were excluded from this study, leaving a total of 225 adult primary OLT patients for analysis. There were 105 female and 120 male patients, respectively. The mean age for the entire group was 49.5 years, 47.4 years for those patients who did not receive RBC transfusions, and 50.2 years for those who did receive RBC transfusions. Techniques for procuring and transplanting the donor liver have been described elsewhere.^9- 11 The mean (±SD) cold ischemia preservation times in the transfused and nontransfused groups were 11.6 ± 0.2 and 10.7 ± 0.4, respectively. The difference was not statistically significant. The 225 OLTs were performed by the following techniques: 169 piggyback (75%), 36 standard with venovenous bypass (16%), and 20 standard without venovenous bypass (9%). Recipients were divided into 2 groups based on intraoperative RBC transfusion requirement. The transfused group included 171 recipients (76%) who received at least 1 U of RBCs intraoperatively, while 54 recipients (24%) received no RBCs (either packed cells or salvaged blood) intraoperatively (nontransfused group). Cell saver was not used in patients requiring less than 30 U of blood. For the effect of RBC transfusion on patient and graft survival, the groups were arbitrarily divided into 3 groups: intraoperative transfusion of 0 (54 patients), 1 to 4 (64 patients), and 5 or more (107 patients) U of RBCs, respectively. The transfused group included 171 recipients (76%) who received at least 1 U of RBCs intraoperatively.

The influence of the following variables on patient and graft survival after OLT were determined by univariate analysis: age, sex, primary diagnosis, medical condition at the time of transplantation, previous abdominal surgery, transjugular intrahepatic portosystemic shunts, preoperative prothrombin time, intraoperative RBC requirement, cold ischemia time, and operative time. The patient's condition at the time of transplantation was based on Child's classification and United Network for Organ Sharing (UNOS) status. Patient and graft survival were also calculated for the transfused and nontransfused groups. Variables that had a substantial effect on patient and graft survival by univariate analysis were entered into a proportional hazards regression analysis along with transfused and nontransfused recipients to determine whether transfusion of packed RBCs was independently associated with survival or whether confounding variables were present.

Univariate analysis was performed by the Mann-Whitney nonparametric test. Patient and graft survival were determined using a log rank (Mantel-Cox) test and Kaplan-Meier cumulative survival plot. A proportional hazards model was used to control for any intergroup differences based on the aforementioned variables found to have a substantial effect on survival. Factors that were significant in univariate (Mann-Whitney) tests (P<.05) were considered in a multivariate proportional hazards regression model. Backward stepwise selection was used to find a group of factors that best influenced outcome. In the first step, all factors that had a significant effect on outcome as determined by univariate analysis were considered. At each step, the factor with the largest P value for significance was removed until only those factors with P < .05 remained. These remaining factors were then considered to be those that were statistically significant in predicting outcome. Statistical software (S-PLUS, Version 3.2, StatSci, Division of MathSoft Inc, Seattle, Wash) was used to perform the logistic regression analysis.

In the present study, the overall patient survival rates were 90% at 1 year and 86% at 3 years, and graft survival rates were 89% at 1 year and 85% at 3 years. Patient and graft survival for patients undergoing OLT with and without intraoperative transfusion of RBCs are shown in Figure 1. Transplant recipients who did not receive RBCs intraoperatively had significantly higher patient and graft survival compared with transfused recipients (P=.01 and P=.03, respectively). However, the following factors were also associated with patient survival: age (P=.04), sex (P=.005), and the patient's medical condition (P=.002). When these factors, along with whether a patient was transfused intraoperatively, were subjected to stepwise multivariate analysis, intraoperative transfusion of RBCs was not significant and only age (P=.03), sex (P=.004), and patient's medical condition (P=.003) remained significant (Table 1). The results of similar univariate and multivariate analyses for graft survival are given in Table 1. Men had poorer survival than women and survival was worse for critically ill patients (status 1 and 2a based on current UNOS classification).

When survival rates were examined, patient and graft survival decreased if 5 U or more were transfused (P=.006 and P=.01, respectively) (Figure 2). When subjected to multivariate analysis along with age, sex, and patient's medical condition, transfusion of 5 U or more was not independently associated with patient or graft survival (Table 2).

Transfusion of packed RBCs, when examined as a continuous variable, was found to influence patient and graft survival by univariate analysis (P<.001). When subjected to multivariate analysis, blood transfusion as a continuous variable remained significant for both patient (P=.008) and graft (P=.03) survival, along with age, sex, and the patient's medical condition (Table 3). Figure 3 shows relative survival as a function of amount of RBC transfusion and demonstrates decreasing survival with increasing transfusion requirement.

When causes of patient and graft loss were examined, only 1 patient died (primary nonfunction) and 1 patient lost a graft (hepatic artery thrombosis) in the nontransfused group. Twenty-nine recipients in the transfused group died, and 45% (13 patients) died of septic complications, including generalized sepsis, endocarditis, aspergillosis, and bacterial pneumonia. The remaining causes of death were cancer (5 patients), cardiovascular disease (3 patients), trauma (3 patients), intraoperative cardiac arrest (2 patients), primary graft nonfunction (2 patients), natural causes (2 patients), and recurrent disease (1 patient). Causes of graft loss in the group included biliary strictures, hepatic artery thrombosis, and primary graft nonfunction, 1 patient each.

Several centers have examined factors that influence patient and graft survival after OLT, but no consensus exists as to which variables accurately predict outcome after OLT.^2- 7 According to these studies, factors that have increased the risk of death or graft loss for patients undergoing OLT vary and include UNOS status, Child's classification, fulminant hepatic failure, ABO incompatibility, compromised renal function, and infection before transplantation. In addition, some studies have reported a detrimental effect of intraoperative blood loss and massive transfusion requirements after liver transplantation.^2- 3,7- 8 In a previous study, we conducted an analysis of several factors on the need for blood transfusion.¹² These factors were recipient's age at the time of transplantation, sex, Child's classification, UNOS status, preoperative hematocrit, prothrombin time, partial thromboplastin time, platelet count, and fibrinogen level. In addition, other factors examined were primary liver disease, year of transplantation, history of abdominal surgery, transjugular intrahepatic portosystemic shunt placed prior to transplantation, use of venovenous bypass technique for transplantation, cold ischemia time, and operative time. The univariate analysis showed the following factors to be associated with OLT without blood transfusions: Child's classification, UNOS status, lack of previous right upper quadrant surgery, preoperative hematocrit, prothrombin time, activated partial thromboplastin time, piggyback technique, operative time, adult recipient status, and year of transplantation. A regression analysis showed that UNOS status (healthier patients required less blood), preoperative hematocrit, piggyback technique, operative time, and year of transplantation remained independently associated with OLT without transfusion of RBCs.¹² Unfortunately, donor information was not available for the analysis.

The present study examined the effect of OLT without transfusion of any RBCs on patient and graft outcome. A significant improvement was noted in both patient and graft survival when recipients underwent OLT without intraoperative transfusion of RBCs. However, other factors, rather than the presence or absence of intraoperative blood transfusions, appear to have a more substantial effect on outcome. Male sex and severity of the patient's medical condition (patients in an intensive care unit) had a negative influence on patient and graft survival. This finding is in agreement with UNOS scientific registry data, which have shown that sex and patient's medical condition affect both patient and graft survival.^1,12

Why OLT without RBCs transfusion was not independently associated with superior patient and graft survival may be related to several factors. Previous studies demonstrating an adverse effect of transfusion requirements on outcome were conducted during an earlier era of OLT and examined the effects of massive intraoperative transfusion of blood and blood products.^2- 3,8 A more recent study also divided patients into a group of "bleeders" who received 10 U or more of RBCs.⁷ The present study compared patients receiving no RBCs with a group who received at least 1 U of RBC intraoperatively, and the study population did not contain a large proportion of bleeders. In fact, 50 patients (29%) in the transfused group received 3 U of packed RBCs or less intraoperatively (mean 5.7 U, median 4.0 U, range 1-67 U). The small number of RBCs required intraoperatively in the present study is probably due to technical improvements in performing OLT. Even when a group of recipients who received 5 U or more of RBCs was examined, an independent association with survival was not seen. Because many patients in the transfused group received few RBCs, the detrimental effect of massive transfusions in the few patients who required it were most likely masked by the remaining patients receiving only a few units of RBCs.

When cutoff points were not employed and blood transfusion was examined as a continuous variable, it did have an independent association with survival. The concept that increased blood loss, and hence, a greater transfusion requirement during the transplantation, affects survival agrees with other data.^2- 3,7 Although blood loss is not the only factor that influences survival, it does point to the need for attention to detail during the procedure.

Previous studies have reported a high mortality rate secondary to infectious complications in general,^13- 14 and particularly in patients who have received blood transfusions.⁷ Almost half the deaths in the present study involved septic complications, similar to the previous studies. In addition, all deaths due to sepsis occurred in the group that received transfusions, and the mean intraoperative RBC transfusion requirement for these patients was 13 U.

The present study demonstrates that recipients who undergo OLT without transfusion of RBCs have superior patient and graft survival when compared with transfusion recipients, but other factors have a substantial effect on outcome after OLT, namely, age, male sex, and medical condition at the time of transplantation. When the effect of intraoperative blood transfusion on survival was examined as a continuous variable, an independent association with survival was noted, suggesting that blood loss should be kept to a minimum during the transplantation.

We thank Katie Allen for the skillful preparation of the manuscript.

Corresponding author: Carlos O. Esquivel, MD, PhD, Professor of Surgery, Stanford University Medical Center, 750 Welch Rd, Suite 319, Palo Alto, CA 94304-1510.